Activation of the Ras signaling pathway has been associated with altered radiation sensitivity in vitro and in vivo. In human tumor cells in which the Ras signaling pathway is activated, inhibition of Ras farnesylation with farnesyltransferase inhibitors (FTI) leads to enhanced radiosensitivity. R115777 is a specific inhibitor of farnesyltransferase that has been studied extensively in the clinic. R115777 is an in vitro and in vivo radiosensitizer and inhibits the Ras signaling pathway. The long-term objective of this project is to develop R115777 in combination with radiotherapy as a targeted therapy for patients with non-small cell lung cancer (NSCLC). The specific aims of this grant are 1) to perform Phase I and Phase II clinical trials of the FTI, R115777 in combination with radiotherapy in patients with unresectable non-small cell lung cancer (NSCLC) and 2) to relate the status of molecular markers in NSCLC tumors to clinical efficacy of R115777 and radiotherapy. In the Phase I clinical study, the maximally tolerated dose (MTD) and recommended Phase II dose (RPTD) of R115777 in combination with standard radiotherapy will be determined. In the Phase II study, the efficacy of R115777 and standard radiotherapy will be determined in patients with locally advanced NSCLC. Specific molecular markers that are associated with activation of the Ras signaling pathway will be measured in NSCLC tumor biopsy specimens and will be related to the clinical efficacy of [unreadable] R115777 and radiotherapy. [unreadable] [unreadable]